Category Archives: KCA Conferences

At a City of Hope Medical Center, teaching hospital/research center, a pharmacist spoke to our patient group about drug interaction. She reminded us that we are responsible to follow the dosages, to alert our doctors to ALL the medications we take–prescribed and over the counter, herbals and supplements. “Remember that diet and its fat content affect our drug’s efficacy”, she added.

Pharmacists consider three types of interactions, which can happen between drug and another, with drugs and food or beverages, and drugs and conditions under which a drug is taken. They are described as follows:

1) Pharmokinectic issues of absorption, distribution, metabolic and excretion—how does the body bring it in, how long is it in the system, and where does it get absorbed? Does one drug slow down the effect, or prevent its use?

2) Pharmocodynamic effects occur when drugs with similar properties to one another are used together. They may interact with one another; such interactions might cause one or more to be ineffective, or too effective, or with side effects that are unexpected.

3) Toxicity may happen if the combinations of drugs have a toxic effect on an organ that would not occur with just one of the drugs.

For example, soranfenib (Nexavar) should be taken without food, while Sutent is recommended to be taken with food—but never with grapefruit juice.

Some drugs cannot be taken with NSAIDS; some are platelet inhibitors, for example. Sutent’s efficacy may be impaired by taking St. John’s wort, or when taken with barbiturates.

How do you keep track of all of this? Speak with the pharmacist whenever you have a change in medication—or right now, since you probably have not done that! Make an appointment to have the time cover all the questions. Bring in ALL the medications you use, even those you feel are “probably” safe or those you are embarrassed to admit you take! Pharmacists have access to extensive data bases, not only of the prescribed drugs, but also many of the supplements and herbals on the market.

As to herbals and supplements, she reminded the group that there are no controls as to the quality and quantity of active ingredients in the non-FDA approved supplements, and they can vary dramatically. Meningitis caused by a fungus in steroids produced by a US-company has caused the death of 44 and sickened at least 600 just last year.

It was fascinating to hear that, “Pharmacists don’t take medications”, but she emphasized that she rarely uses anything. It’s harder to convince her mother! Anticipating problems in the future with family-related conditions, she eats properly and exercises, for example.

Trust your gut about your body’s reactions. If something seems amiss, talk to your pharmacist or doctor to be sure you are not having a drug interaction.

Read the labels and follow the instructions. Not sure when and how much to take? Go back to the pharmacist or doctor for clear instructions.

Bring a “brown bag” of meds and such to your pharmacist to get a review of your meds. You know you should have already done this, so get going!

I am presenting for Dr. Bukowksi (of Cleveland Clinic Taussig Cancer Institute) and this is his outline. It is not so much about novel therapies, but about clinical trials, why they are important.

Clinical trials, what’s in it for you? We talked about it for the field, but what is in it for the patients who might want to consider a trial? What is a clinical trial?

“A study conducted to allow safety and efficacy data to be collected for a health intervention such as a drug, device, or treatment protocol”, as per the slide.

They are designed on a certain ethical code of conduct which we follow very closely. They are monitored very closely, followed by people, both internally and externally, the FDA and IRB, the Institutional Review Boards at our institutions.

This list– I thought this was pretty funny– that Dr. Bukowski came up with is from a Persian physician, on the ways to conduct a clinical trial, from 1025 AD, a thousand years ago. I don’t know how many clinical trials were done a thousand years ago, but I thought the last one was pretty good, “The experimentation must be done on a human body, for testing on a lion or a horse may not prove anything about its effect on man.” We talk a lot about morbidities or complications on people on clinical trials; I can’t imagine being the investigator on any lion trial! Probably higher risk for the investigators than the lions. I’m glad we made advances in the last thousand years.

This is one of the more famous clinical trials, given by James Lind in 1747. He was given the task, and first to show that citrus fruits could cure scurvy. He did what was like a randomized trial, comparing the effects of various acidic substances, citrus fruits or cider– gave them to sailors with scurvy, essentially proving that giving oranges and lemons can give quick recovery in patients with vitamin C deficiency. He is one of the founding fathers of our field of clinical investigations. We’ve come a long way since then.

As far as types of clinical trial, some are conducted in different ways. Some are what we call observational, meaning we collect data that other researcher use to study patterns, to study outcomes over the long period time, things like risks for heart disease. For this group, we often do something for patients, usually with a device or a therapy, and this usually compared to a group receiving no therapy, no treatment, or commonly, the old standard of treatment of care.

There can be many different purposes for trials. Some can be for screening, some are preventative, which we haven’t talked about much yet, but can improve the way we diagnose kidney cancer. So there are many different types of trials.

You want to ask, “What phase is this?” The reason that is important is that each phase of testing has a different goal. I will focus on the middle ones here; Phase I often focuses on the drug safety. It has traditionally been about, “What’s the right dose of the drug? What’s the right schedule for the drug?” Traditionally, Phase I trials have not always been great for the patients, as the main focus is “What’s the safest way to give the drug?”, not whether the drug is effective. They were often left for patients with fewer or other options, when everything else had run out, you would consider a Phase I trial.

But nowadays, Phase I trials are changing somewhat. They are often not open for patients with just any kind of cancer. They are open for patients with specific kinds of cancer, because there is already some sense that this drug looked interesting in the laboratory, that it might be effective for a specific type of cancer. W aremore focused in that regard. We are also testing patients for certain tumor characteristics, so getting a sense, not of what kind of cancer they have, but what kind of tumor do they have, what kind of genetic changes are going on in that tumor. Most importantly, some phase I trials—once they get the safe dose—are doing what is called “dose expansion”, where they take patients with specific tumor types and treat them all with the same dose. This is essentially doing a Phase II trial within a Phase I trial, though a smaller Phase II trial. In many ways, there is an advantage on the being on that kind of trial, in my admittedly biased opinion, because you know you are getting a drug that has shown in many cases some sense of safety and activity. It is certainly something you should consider, not necessarily right off, just because your doctor wants to consider you for a Phase I trial.

Phase II trials’ main focus there is the effectiveness; how effective is the treatment? They usual focus on some single cancer type.

Phase III trials are a more comparative trial. It’s comparing something that is new to an older or the standard treatment. For many years, the “new” was really no better than the old, but one of the things that more recently, is that a lot of the new has been better and we often have had a sense that it was better, before we got to confirm it in trials.

One of the uncomfortable things about a Phase III trial, from a patient’s point of view is the randomization. It makes them very anxious. You lose a certain amount of control, both the physician and the patient, about what you are going to receive. So a lot of people choose not to go on a Phase III trial because they are uncomfortable with that process. The way I like to look at, not as a patient’s perspective, even in a randomized trial is that you get a 50% chance at trying a new agent earlier. That may not be worth it to you, but it’s worth a discussion, a consideration as you go through treatment. There often are also trials that come after the drugs has been approved, like expanded access trials, where they offer it to patients just to test further questions, safety, for example.

We talked a little bit about clinical trials, and some of the caveats, about randomized trials and how that can throw people off. Like randomization: It turns out that this is the only way we know if a new treatment is effected. As many flaws as there might be from a patient’s perspective, it is here to stay. At least for the time being, we are going to have randomized trials.

One other concept that often also throws people off is whether the trial is blinded, that is, where the researcher and the patient may not what the patient is getting. Why is that? The reason is that because if you know what someone is receiving, you might make judgments that bias the outcome, both on the patient’s side and the physician’s side. A lot of people don’t like not knowing what they are getting.

PLACEBOS

The one thing that throws the most wrenches into this is the whole concept of a placebo as a control arm, and unnerves a lot of people for good reason. You are going to to be told if a placebo is involved, number one, for sure, up front. Now that we have effective drugs, placebo-controls are less likely to be acceptable options. Meaning, they are only acceptable if there is no standard treatment, so 5-6 years ago, when there was no or very few standard treatments for kidney cancer, we relied on placebos.

Now these are being compared to active treatments. So you are either getting active treatment A or active treatment B, comparing it to a new treatment. Going forward in kidney cancer, there will probably be fewer and fewer placebo-controlled trials.

Here’s a list; you’ve seen this before; all the important trials that they have done in the last ten years. The important thing about this is that is patient involvement that has made this progress possible. This is a look at 8-9 trials that have enrolled 4000-5000 patients. It is quite a long list of progress, made only by patients with a willingness to so, so it is important to encourage people that you may communicate with online or in your email to consider participation. It is only through that participation do we make this kind of progress. Clearly we have more progress to go.

So summarizing our recent advances, to show that we can shrink tumor in 10% up to 50% of patients in these newly targeted agents. As Dr. Jonasch was talking about, we can surely slow tumor growth which leads to lengthening of survival. Patients are living longer, Hutson says 3-5 times longer. My patients are living years longer than they used to in the past, but we are still not receiving enough remissions. We need to work on getting remissions, once the treatments have stopped.

We talked about participation, we need to do that to improve outcomes. We need to better understand the biology of kidney cancer, as Dr. Jonasch was talking about, to identify patients before they get treatment, and to assign them to treatment that is likely to help them. It is only through that–not just clinical research, but also laboratory research– that we will be able to do that in combination. We need to increase the funding for those endeavors, as it is rather expensive, at a time when the NCI’s budget is fairly tight.

You hear a lot about personalized medicine in the treatment of cancer, but we are not yet in the era of personalized medicine for kidney cancer. We are making certain decisions, but they are based on fairly rough guidelines, but we are making decisions based on whether a patient has been treated or untreated. We are trying to assign to patients to certain risk categories based on certain features of that suggest a good or a poor prognosis. We are making decisions, as we talked about earlier, on whether a patient has clear cell or non-clear cells, but these are very rough sort of guidelines. We need better ones, obviously and we are hoping to come up with better ones, based on the patients’ own genetic profile and the profile of the genetics of the tumor. There is a lot of work going on in that as we speak.

Recently reported trials; these are trials reported in the last year.

Not all trials are positive. The first is called the Renal Effect Trial, randomizing patients to either prescribing the intermittent dosing of Sunitinib versus the continuous dosing of Sutent. The hope was that giving the drug at a lower dose continuously that the treatment would be more tolerable or more effective. It turns out that there was no difference, so they could be used interchangeably.

There was a second trial with Sorafenib, where they added on another anti-angiogenesis inhibitor, in hope of improvement with the standard drug, Sorafenib. It’s the trial in the middle there, and unfortunately, the additional drug did not improve outcomes to the Sorafenib.

The last trial on the bottom, that both Dr. Hutson and Dr. Jonasch mentioned was a Phase III trial, once again a randomized trial that comparing—not a placebo—but a standard of care, Sorafenib to a new therapy, axitinib, which proved clearly that axitinib was a step forward. It may be a small step forward, but it is important for our patients. That led the FDA to approving this new, hopefully, second generation anti-angiogenesis drug for our patients earlier this year.

So what’s coming? Hopefully, drugs that are less toxic and more effective. There are a series of Phase II and III trials that are coming close to reporting their results you will be hearing about them in the next year.

Their names you see here: COMPARZ, RECORD 3, TIVO1, you’ve heard a bit about, TORISEL 404. We talk a little bit about these, what we can expect from these trials. We can also talk a little bit about targeted immunotherapies, vaccines and ultimately, combinations that might make sense. All these are being tested and in the next year, we’ll know a lot more.

There are several trials, trying to improve upon Sunitinib, which is the most prescribed treatment for patients with metastatic kidney cancer in 2012. The COMPARZ trial is comparing Sunitinib with Pazopanib, which is Votrient. The makers of Votrient would hope show that it is as effective as Sutent, and perhaps less toxic. We’ll see that result later this year. Obviously, drugs that are less toxic are worth developing.

The other trial looks at the proper sequencing of the RECORD trial. Should you start with Sutent and move to Afinitor, or start with Afinitor and then move to Sutent? We should get some information on the proper use of Sutent, hopefully, with the RECORD 3 result

We mentioned the AXIS trial which compared axitinib to Sorafenib and led to Axitinib’s approval. That was a step forward.

Hopefully there will be another step forward in the second line setting, which is this new -1, a second generation of anti-angiogenesis inhibitors. This TIVO-1 trial which Eric (Jonasch) mentioned targets a new, more specific antiangiogenesis inhibitor , comparing Pazopanib to Sorafenib, showing it was more effective, so once again, we are coming with better agents than five year ago.

Another important trial will compare an mTOR inhibitor to Sorafenib again, Torisel to Sorafenib standard and to answer the question, when you fail a prior treatment like Sutent, what is better—to give you a another drug like Sutent, or to give you a completely different approach—which is the Torisel drug. We’ll be learning a little bit more about the proper sequencing of these agents. All of this information should be available coming soon.

The Tivozonib data will be presented at ASCO in June and hopefully the Torisel data will be presented later this year.

Combinations of drugs; most oncologists think that if one drug is good, two have got to be better. There have been a lot of combination trials done this far. Most have been, I must say, somewhat disappointing, and we will talk about why that is. Hopefully, as we get less toxic agents, we will bet smarter about putting these things together, and we will make some progress. These are some of the drugs that have been used in combination.

Laboratory trials have suggested these: we don’t just do these willy-nilly. Laboratory studies have often shown that two drugs are better than one, but there are several important issues. One of these is cost. You all know that these are not cheap. The other is toxicity, and so far, most of these combinations have proved pretty toxic when given together. Here are two trials that are looking at a blood vessel strategy with mTOR inhibitors. The RECORD 2 trial looks at Bevacizumab and Everolimus together versus the standard of Bevacizumab and interferon; the INTORACT trial looks at Bevacizumab and Temsirolimus together. These are both large trials that will give us the answer to whether two approaches to attacking the cancer better than just one at a time. We’ll see that going forward.

As you know, as we talked about things today, that none of/very few of these drugs produce complete remissions, and we obviously need second- and third-line treatments.

There are a couple of trials accruing that will give us some answers to that. There is another antiangiogenesis inhibitors, the TKI-258 (references on left), and it is in phase III trials, once again comparing to Sorafenib, so that might be a step forward as well. Looking at this Phase 3, looking at this Cooperative Group Trial, looking at combinations, adding Bevacizumab, hoping that will aid in outcomes with what Everolimus does. We’ll see.

We’ve talked about vaccine treatments, and I alluded to one trial, the ARGOS III trial, looking at combinations of vaccine and Sutent. It is more than one trial, it is the IMMATICS trial on the right,; it looks at another peptide vaccine, also in combination with Sunitinib. Hopefully it will lead to more durable benefit with this drug. It is great that we are in large Phase III trials, as this will give us answers, but the answers are still a long way away, as these trials are still enrolling patients.

We mentioned the PD Antibody earlier. This is one of the more exciting ones of the targeted therapies being developed. Two things I did not mention this morning that I want to make now, is that this drug will soon be entering Phase III trials. It’s moving pretty quickly, and hopefully Phase III trials will open later this year, and if positive, might lead to the drug’s approval.

But just as important, there is more than just one PD or PD L drug in development. These are five separate companies, all of whom have decided it is important to find different way to block the “barbed wire” that I talked about, that protect cells from the attack by the immune system. You will hear more about these agents, not just in kidney cancer, but in other tumor types as the year goes on.Chris Wood covered this very well earlier, so I won’t address that, but we are also doing clinical trials with drugs that have been used with Stage IV patients, we are now using those with Stage II and III patients. And as he (Wood) said, it will take several years before we know if it will delay cancer from coming back after surgery, or will prevent cancer from coming back after surgery—there’s a big difference with those two. We are several years away from knowing those results. But the great news about these trials is that they are accruing well. Patients have gone on them very quickly, much more quickly that we expected, though the drugs may have issues for the patients, side effects…..we will have to see about the effectiveness. The patient community if very motivated to go on trials like this, so hopefully as we get better drugs, we can test them in patients in the early stages of kidney cancer and prevent recurrences. That’s where we can have a huge impact, preventing the need for treatment for Stage IV cancer.

So, in closing this is obviously one fundamental question for folks who have not considered a clinical trial. Obviously I am biased, incredibly biased, as it is what I do. I think it gives you access to cutting edge approaches. Obviously the newest thing isn’t always better, and sometimes it is harmful and we’ve seen multiple cases of that. But I do think you get access to things sooner if you consider trials.

And I do think we are getting better, as I mentioned, picking treatments than we were ten years ago, and also picking patients for those treatments. We are a little bit smarter. We are having more positive trials.

But all that being said, the participation of patients in the US in clinical trials is still less than 3% of patients. So when you think about it, I can sit up here all day and talk about all the things I want to do, and Eric (Jonasch) has great ideas, and Tom (Hutson) has great ideas, and Chris Wood’s ideas are OK (smiling), but we can’t do it without participation and convincing people to come and sacrifice, as there are costs to travel and risks . It takes a lot and really requires a mobilization of the whole kidney cancer community. I hope that this will increase the willingness to participate in clinical trials to get the message out about why it is important. There a lot of reasons why you might want to consider it, but people ask, What else is in it for me?” I know what is in it for me, and for the field, but what else is in it for me personally?”

There are some people who think that the care on clinical trials is better. You can argue that back and forth, but you are certainly followed much more closely on a clinical trial that you wouldn’t be if you were not on a trial. You are not only being watched more closely for side effects, you are watched very carefully to see if the treatment is working. There are a lot of rules set up to protect you, not only from the side effects, but from ineffective treatment. There are rules by which we have to remove you from your trial if it is not in your interest. Most importantly, you can always stop at any time, once you join a clinical trial.

The other question which is a little bit harder to address is whether patients on clinical trials do better, and he has some interesting data

data that was presented last year. This is looking at 238 phase III clinical trials of all cancers done in recent years. When you look at this slide, and it’s a little bit complicated, I didn’t want to get too much data in it, but it is kind of important..

For the 158 trials that reached their goal, where they reached the sufficient number of patients, Sufficient Accrual, that was 2/3 of phase III trials. So not all phase III trials reached their goals of accrual of patients, which is a problem. But of those that did, most of those trials showed positive results, in fact, 143 of 158 had positive results. There were some that had negative results, closed early, or had side effect of toxicity. But it was a relatively small number, only 15% on this slide. The highest reason for trials not succeeding was that they did not get enough patients on them.

This makes a couple points. One, we’ve got to get more patients on trials, so we can answer these questions. Second, a lot of the trials that we are doing help advance the field, but we think help the patients who go on them. That would be hard to prove, but it is certainly worth considering. There may be some advantages for you as an individual when you are considering going on a clinical trial.

So in conclusion, clinical trials advance our knowledge and have improved outcomes in kidney cancer. It has been a great effort by many patients. Six thousand patients have gone on these trials that we have talked about over the day, not only improving outcomes for themselves, but also for future ways we treat patients. Coming up with better way to treat patients is only going to happen with research. We need to keep working on it, to define new approaches, we need to extend treatment earlier in disease, and we need to focus on patients who are unable, or don’t qualify for trials. We need to do a lot more work in that area, but hopefully, in partnership we can make advances, like we have in this last ten years.

End of Lecture; Questions from patients and caregivers follow.

Questions;

ACOR list member has asked about XL 184. How optimistic are you about XL 184 having activity in bone lesions, as well as soft tissue lesions; also, as far as imaging, she would be concerned about masking of bony lesions on imaging. On recent studies, ie, questions whether bone scans are the best measure of activity of XL 184.

That is a pretty sophisticated question, and in my earlier talk, I got a questions about XL 184 and I think this. In kidney cancer, it has only been through Phase I testing, so I think it is a little early to know how active it is. But there are really people in our community that really want to study it. The focus is not only the VEGF but the protein that Dr. Jonasch mentioned, that MET protein which is thought to be an important driver in all cancers, and kidney cancer. Certainly we want to study it. It’s been tested mostly in prostate cancer, and they’ve seen some impressive results. We’ve seen that in prostate cancer, but whether we will see that in kidney cancer, that remains to be proven. That would be an advance, something that would control bone metastases. That would be exciting, since a lot of our drugs fail in bone. But it would need to be tested. I couldn’t agree with that more. How well it will be tested, that remains to be seen. Dr. Tannir may be talking of this class of drugs in his talk.

Soft tissue metastases, any activity in that? I know we’ve seen activity with the bone mets, but soft tissues?

Answer: It is to early to say that we have seen that, but that is certainly the story in prostate but we don’t know yet in kidney cancer. But you will see a presentation at ASCO, where you will get a sense of how well it’s working in kidney cancer, but it’s going to be a very small trial. We need a much bigger trial.

This is a more general question, and I never hear anything about it. Is anyone collecting data on your outliers, those people who survived the interleukin 2, IL, or data, anything to see if there is something homogeneous about them or any attributes? I just never hear anything about this.

DO you mean people who can’t go on trials, or people who do really great?

Those who do really great, those with long PFS or OS, people

There are people who are thinking about those questions and there are more often cases, where when people present, their tissues or blood and tumor stored for analysis so we may be able to do that kind of study in the future. There are people who are looking at genetic predictor of response to treatment but right now there are no great predictors of response to these agents. We need to do a lot more work on that. We don’t understand why there are great responders—yet. We have the capability of learning about that now we are collecting information.

I just wonder if it is lack of patients or lack of money, if there is no big drug involved.

Any research will say there is lack of money, we could also do with more money. There is also a lack of insight. If we have the information, can we tease out what it is important. I think Dr. Jonasch is going to save me with an intelligent answer.

Jonasch: I don’t know if it will be intelligent, but it is an answer! Anderson has an unusual responders program, and what is to be done, and Dr. Tannir and I are both participating in that. We are taking those with outstandingly good and outstandingly bad responses, and we are performing sequencing analysis to get clue to determine what exactly makes those people different. Hopefully I am getting my data back in the the next month or so, with individual are treated with Sunitinib. So it will give us some ideas , to understand those differences. So, no answer yet, but work underway.

I don’t want to be morbid, but want to understand. You have just said about sending tissue, is that at the end of your life or?

It’s usually at the time of diagnosis, so Anderson is great example of this. They will ask you after the tumor is removed, after Dr. Wood removes it, can we have a piece for our tissue bank? They will save it, save it in an impersonal way, and they will use samples from your body, not just the tumor, your urine or your blood, things like that and track your outcomes, along with a large number of people. By donating that tissue upfront, it is a lot more useful and we can get a lot more information about your tumor if we can get a fresh piece of tumor. We like fresh tumor. We’ll take anything, but fresh is better.

I am asking a question which may have explained a bit earlier,how the patient is handling side effects and how that puts a greater responsibility on the patient. How is a patient who is not able to come to a place like MD Anderson or these other center. How is a patient able to help guide or cooperate with his local oncologist and handle this massive amount of information and differentiate whether he is getting the best treatment possible.

OK, that is a complicated question, For the most part, now that we are 5-6 years into these new agents, most oncologists are making good treatment decisions. In the case where you are not sure, you’re unsure, you can always ask, “Can I get another opinion?” I think most oncologists don’t feel awkward about that. “Is there someone you can call to ask about my side effects? Is there someone you might send me to for this next treatment decision? These days, the good news is that you can end up receiving a lot of your treatment close to home, since these drugs are approved, but getting a confirmation is sometimes helpful, just for piece of mind. Most oncologists that I work with are pretty comfortable making that referral. Going through your doctor is a lot more productive than going around. That’s my personal experience. They get experience, they work in tandem, which is better than losing track of the local person.

So we could predict who was going to respond in the primary tumor, so the question was, “Can we use that as some sort of bio-marker?”

PART Two of Several Parts;

“Cytoreductive Surgery for Metastatic RCC: It’s Not for Everyone”

Dr. Christopher Wood

Integration of Surgery and Systemic Therapy in the Treatment of Kidney Cancer

Also referred to in the KCA program as “Role of Cytoreductive Surgery in the Treatment of Metastatic RCC

UT MD Anderson Cancer Center

April 14, 2012; KCA National Patient Conference

Cytoreductive Surgery for Metastatic RCC: It’s Not for Everyone

Identifying Patients Who Will Not Benefit from Cytoreductive Nephrectomy

Cytoreductive surgery is not for everyone. Certain patients will not benefit from surgery. We (MD Anderson) did a study to see if we could accurately select those patients who would not benefit from such a surgery, to save them from a surgery likely to be highly morbid and not beneficial. We compared 566 patients undergoing surgery to a group of 110 patients were treated with their tumors in place and treated with medical therapy only.

We tried to predict for which (patient) factors predicted outcome. We at MD Anderson can be very aggressive in our surgeries as we believe in cytoreductive surgery, so these patients who could not have surgery were probably the worst of the worst. For these patients, treated with medical therapy only, the median survival was only 8.5 months.

With that in mind, we looked at those patients who underwent surgery. If those patients did not live beyond 8.5 months after surgery, they probably did not benefit from that surgery. What factors predicted for those patients to live longer than the 8.5 months than did the medical therapy alone group?

What factors would be predictive of how one would do? We identified the above factors; low serum albumin, an overall nutritional status lab value, elevated LDH, also a blood test, the presence of liver mets, presence of symptoms due to those metastases, retroperitoneal lymph node involvement, (discussed earlier as a bad sign),supra-diaphragmatic lymph nodes and locally advanced T state. All of these features predicted for a worse outcome.

If a surgical patient had three or fewer of those features, he did significantly better than those who received medical therapy alone. But if a surgical patient had more than three of these features, that outcome was the same or worse than those who received medical therapy alone. So now we are using these features to prospectively select patients for surgery.

Can We Do Better?

Is the relevant question whether or not surgery should be incorporated into the management of metastatic kidney cancer?

I argue the more relevant question is whether there is a role for “pre-surgical therapy” for metastatic kidney cancer.

Pre-surgical therapy means to give some targeted therapy for some defined period of time, then go to surgery and resume targeted therapy after surgery. The potential benefit may be to use the pre-therapy as a selection process: patients who do well are those taken to surgery, and the ones not doing well are spared a surgery that not likely to give them benefit. It allows us to harvest (surgical) tissue that has been treated with these agents. With that available, we can study it to see how targeted therapy affects the tumor, what pathways are turned on and off, to help generate the next treatments. It may shrink the primary tumor and make the surgery easier, most important this is that it allows us to spare patients from surgery that they are not likely to benefit from.

However, targeted therapies don’t just target the tumor. They also target wound healing, which is why many patients who get this therapy have wound complications. The tumor will not respond to the therapy and may grow; a patient who was a surgical candidate all of a sudden becomes not a candidate for surgery, because the tumor has grown. He may need a more extensive surgery. The more I take out, the more difficult it is for you. And timing is everything. If you get targeted therapy and respond well, why stop that to send you to surgery? And as a surgeon, if you are not responding to targeted therapy, why would I want to take you to surgery?

Potential benefits are that the primary tumor may shrink, may downstage or downsize, and make surgery easier. Maybe we could do partial nephrectomies on everybody, save some kidneys. It may make the unresectable become resectable. It may improve prognosis. In patients without metastatic disease, it may eliminate micro-metastatic disease. (Pre-surgical targeted) therapy might be used as a litmus test of response, but there are risks, including surgical morbidity and lack of response. Plus there is pre-clinical data which suggests that in some cases, targeted therapy, treated in this fashion, may make the biology of the disease worse.

This is the MD Anderson trial with Bevacizumab (Avastin), where patients were treated with Bevacizumab for two courses of treatment and then went on to surgery and back on Bevacizumab after surgery.

We recently completed this Sunitinib trial. Patients completed two courses of Sunitinib, followed by nephrectomy and went on to receive Sunitinib post operatively when they had a response.

This is my Axitinib trial, where patients with locally advanced disease would receive three months of Axitinib, and go on to get a curative nephrectomy

Dr. Kamar showed you earlier an evolution in surgery over time. Ten years ago, everyone got an open nephrectomy; it was done open and very morbid. Then people began to use a partial nephrectomy and then a laparoscopic nephrectomy.

Each advance had to prove it was equivalent to the existing technique doing then and each had to show oncologic equipoise, i.e., equivalent cancer control. To give equivalent cancer control was the most important hurdle for each advance in order to be accepted. It also had to spare nephrons, for me, that the least important thing was this it was minimally invasive. Between a minimally invasive operation that doesn’t work, and a maximally invasive operation that does work, which one would you choose?

Similarly this neoadjuvant approach has hurdles. It must be safe and it must have improved outcomes. The least important is that it downsize or downstage the tumor. It is the rare patient who presents that you can’t resect. It would be nice if the tumor shrank, but that is the least important, I think.

Is NeoAdjuvant Therapy Safe?

Is neoadjuvant therapy safe? This patient (on the left) went on Sunitinib, had surgery and went on to get Sunitinib after surgery. What I did not know as the surgeon, that the patient started Sunitinib two weeks after surgery. And he had complete abdominal wall dehiscence (opening of the wound). That is his greater omentum sitting on his abdominal wall. The patient did not even realize that he had a problem and went to the MRI for his repeat staging study. He had no idea that he had a problem, so went he came to clinic and we saw that we went, “Oh, my God!”

Referencing another slide not shown here: On the right is a patient on the bevacizumab trial who had abdominal wall dehiscence, four months out from surgery. That is her small bowel (referencing upper portion of CT scan) and you can actually see it on the abdominal wall.

“Is this safe?” We did a retrospective study on 70 patients using pre-surgical therapy and compared them to 103 patients who had upfront cytoreductive surgery, and we looked at complications over 12 months.

Patients who had pre-surgery treatment did not have more complications than those who had upfront surgery, nor were there more severe complications. However, they were more likely to have late complications, and to have more than one complication if they had a complication. They were more likely to have wound complications, related to the targeted therapy and wound healing.

Looking at a multi-variate analysis, all the factors that predict for poor wound healing, the only factor that was significant was pre-surgical therapy.

Thus patients who get this therapy before surgery have a higher risk of wound complications—but not a higher risk of overall complications. They have a higher risk of wound complications, but for overall complications, it is the exact same risk as patients who got upfront surgery.

Patients who had a decline in their serum albumin while they were being treated had greater problems with wound complications. Serum albumin is seen as a marker for nutritional status. Now we follow that variable and find that for patients who have serum albumin decline, we are more likely to reinforce their wounds with surgery.

Happily, patients who received pre-surgical therapy did not have a worse survival than those who had upfront surgery, followed by systemic therapy. They may not do better, but they do not do worse, and that is an important feature and shown here graphically.

So What About Tumor Downstaging/Downsizing?

In the era of classical immunotherapy with interferon and IL2, with the primary tumor in place, the primary tumor never responded. That in part, was the impetus to take us to cytoreductive tumor, since the primary never responded.

These patients were treated here at MD Anderson. This is a patient had a very locally advanced tumor, and very large lymph nodes. Had this been done as cytoreductive upfront surgery, it would be a huge operation. Treated with Sunitinib and he had dramatic regression in the primary tumor, the nodes all went away, and he was able to have a laparoscopic nephrectomy. Arguably, he benefited from this approach.

This patient was treated with Axitinib for a very large locally advanced primary tumor here, treated with Axitinib, (on right CT). On the right, there was dramatic regression of the tumor.

Here’s a look at the specimen we removed. Here is the tumor sitting in the kidney right here, and arguably, this patient could have been treated with a partial nephrectomy. We wanted to do that, but they were reluctant.

This is another patient treated with Axitinib, that received neoadjuvant therapy, and again you can see (on left) a very large locally advanced tumor sitting in the right kidney. He received Axitinib and after three months, and you see a dramatic regression (right CT). With this he would have had to receive an open nephrectomy and with this, this patient can undergo a laporascopic nephrectomy. Much less morbid.

Here’s a picture of the specimen, dramatic improvement. All of this used to be viable tumor, nowhas been killed by the Axitinib and this rim is the tumor present.

Are These Just Anecdotes, or Can We Rely on These Agents to Downstage Tumors?

I would argue that if it is true, as a surgeon, I would say, give it to everybody. Maybe we can offer partial nephrectomies to all our patients.

S

So what is the data? This study looked at 17 patients treated with their primary tumor in place with Sunitinib. Only 23% of the patients actually demonstrated had a response, but those that did had a response rate of 31%.

At the Cleveland Clinic, the patients were treated with Sunitinib, and the overwhelming majority had little or no response in their primary tumor. In some patients, their tumor grew while on treatment.

Data from our Bevacizumab trial shows the recurrent theme; the overwhelming majority of patients had little or no response in their primary tumor to targeted therapy.

The University of North Carolina tested Sorafenib. Again, there were some dramatic regressions, there were some dramatic progressions, but the vast majority of patients had little or no response in their primary tumor.

Trying to determine once and for all, we want to ask whether there should be this treatment with the tumor in place.

In a larger study of 168 patients treated with tumor in place, we looked to see there would be tumor shrinkage.

Reasons for not removing the tumor is below, with the vast majority not considered good candidates for surgery, or were enrolled in a clinical trial.

These were the therapies they received. The vast majority received Sunitinib, which is the frontline standard of care, with other therapies intermingled.

As to the response rates, we had some patients who had dramatic progression of their tumor, some patients who had dramatic regression of their tumor. The vast majority of the patients had little or no response in their primary tumor.

One of the things that is common in the community is that patients with large venous tumor thrombi may hear their community oncologist say, “Here, take this medication, it will shrink your thrombus and it will make your surgery easier.” So is this data true?

A significant patients will present to me on Sunitinib. In this series, 48 patients had different levels of tumor thrombi and were treated with these agents.

Unfortunately, a recurrent theme (references “Stable Disease in 75%), patients had little or no response in their tumor thrombus. In fact, 15% of patients progressed while in treatment. Only 10% of patients demonstrated shrinkage in their venous thrombus in response to treatment.

Initial Body of Evidence Would Suggest that Significant Primary Tumor Downstaging Will NOT Be Realized with the Current Generation of Targeted Therapy Agents

I would suggest that the initial body of evidence suggests that significant primary tumor downstaging will not be realized with the current generation of targeted therapy. Nevertheless I must confess that I have been quite impressed with the responses that we have been seeing with Axitinib. Every patient has had a response.

As to the report card on presurgical/neoadjuvant therapy. I would argue that it is indeed safe. We see more wound complications, but those are pretty easily dealt with. It does not seem to reliably downsize tumors. I would this does not. Is this worth doing? Should we continue to do this clinical research at MD Anderson and around the world to determine if neoadjuvant therapy has a role in the treatment of patients? I would argue that it does for the following reasons.

In our Bevacizumab trial, 50 patients were enrolled, but only 42 underwent nephrectomy. Six patients had disease progression and went on to salvage systemic therapy rather than nephrectomy. These six patients were saved from a surgery that would not benefit them.

In our series, we asked, “Is there something about pre-surgical therapy that we can use to predict prognosis, and can we use the primary tumor as a bio-marker to predict outcome?”

This is a spidergram looking at primary response in the tumor. We noted is that patients, who did respond in their primary tumor, they responded early. If you don’t see it early, you will not see it; there is no sense to continue treatment if you don’t see some shrinkage.

Those patients who had at least a 10% reduction (in the first 60 days) in their primary tumor size went on to have their tumor shrink almost 25%. If patients did not have that 10% in the first 60 days, they were likely to have little, if any response.

So we could predict who was going to respond in the primary tumor, so the question was, “Can we use that as some sort of bio-marker?”

We treated 75 patients with Sunitinib with their primary tumor in place, and we found that those patients who had a greater than 10% response in their primary tumor had a significantly greater survival than those patients who did not have that early shrinkage of greater than 10%. If they had a greater than 10% response within 60 days, their survival was even better.

And that was in univariable analysis, and it also held up in multivariable analysis.

For the first time, looking at the primary tumor’s response to targeted therapy could be used as a prognostic variable for outcome of patients.

In Europe, there was another study, looking at Sunitinib. They arrived independently at the same conclusion that we did, that those patients (treated with their primary tumor in place) with a greater than 10% response in their primary tumor, when treated with their primary in place, had a significantly better outcome than those treated patients who did not.

Cytoreductive Nephrectomy for Metastatic RCC in The Era of Targeted Therapy

Not a question of “IF” but “WHEN”?

I argue that cytoreductive nephrectomy is not a question of “if”, but really more a question of “When?”

58

This trial that is currently ongoing in Europe through the ERTC, the CERTIME trial. Patients are randomized to cytoreductive nephrectomy followed by Sunitinib versus two course of Sunitinib followed by nephrectomy. This examines timing of the nephrectomy, not whether we should be doing a nephrectomy. This is a much more relevant research question, and this trial is accruing quite nicely over there.

In conclusion, targeted therapy has dramatically improved the outcomes for patients with metastatic RCC. Efficacy in the adjuvant and neoadjuvant setting still is under investigation. Without complete responses from this targeted therapy, surgery will remain an integral part of a multi-disciplinary approach, both as to control of the primary tumor and as metastasectomy. Show me an agent that demonstrates reliable and complete response, I will be the first to argue that we need to reexamine the paradigm.

Do not think that pre-surgical therapy is the standard of care. It is not. It has merit, but it needs further study and validation. It is not clear to me when it is appropriate to integrate surgery into the context of receiving systemic therapy. Thank you very much for your attention.

END OF LECTURE>

Questions and responses from audience.

Audience. “My question is regard to your last comment, as to the immediate impact of say, Sutent, showing up prior to surgery with an early response, does that also mean that Sutent–having a response in metastatic disease–does that tell you than an early response also means a generally better outcome?

Dr. Wood: I’ve got to tell you we haven’t looked at that, but that is a very worthwhile study to do. Intuitively, my answer would be yes, but I don’t think that we have anyone who has done a formal study on that. It is a very good question.

Audience: “How should ablation and the small tumors be monitored if you have those small tumors like less than 3 cm, like if you are a tumor producer, if you have “multi-foci” tumors?”

Dr. Kamar: Do you mean after or before the ablation?

Audience: “Before the ablation.”

Dr. Kamar: While you are on active surveillance?

Audience: “Yes, and if you have multiple primary tumors less than 3 cm.”

Dr. Kamar: This is more common in patients who have VHL syndrome, which is a syndrome where patients have a tendency to have more than one tumor in their kidneys. The follow up is every six months or so, so we don’t really want to image too often for the radiation risks that are involved with doing too many CT scans. Initially every 3-6 months and after the first year, move to every six months or one year. It also depends on whether the patient is young and healthy and why would we want to observe. In VHL patients that is done commonly, because we wait for the tumors to become 3 centimeters before we intervene. We don’t want to do surgery when the tumors are only 1-2cm in that particular patient population.

Wood; The 3cm we are talking about comes from the NCI where they have a huge experience in treating genetic kidney cancer, and they noted that patients with tumors 3cm or less never metastasize. So we use that 3cm size as a sort of trigger to tell us when we need to do surgery. With multi-foci disease, once it hits that 3 cm size, we will go in and debulk the tumors from the kidney, take all the tumors we can take out, and then follow them over time.

Audience: “I have a question re ablation. Is that an option if you have metastasized to your lungs?”

Dr. Kamar: You mean to use it on the lung tumor? (Yes) Do you mean on the mets or do you mean on the tumor in the kidney.

Audience: “No, my kidney is gone, but I have metastasized to the lung, and I have had cyberknife, but is it an option to be used on the lungs.”

Dr. Kamar: I think it is an option, but typically, if it is doable by surgery, which is the preferred way. The ablations that are done outside the kidney are mostly done for bone lesions, where cyroablation of RFA is done, because it is typically harder to remove a lesion from the bone than it is from the lung, for example. It is more commonly done for liver metastases if anything

Wood: It is more common to use it to treat symptomatic metastases, but there is some interesting work going on here at MD Anderson by one of our colleagues, where there may be some immunologic phenomena associated with ablation. We have some case studies that have been done, where patients who have undergone ablation, particularly RFA, not so much Cryo and had a complete regression of their metastatic disease, almost like a vaccine had been put on the met, and actually Seren is studying that with alone and with some of the immunologic agents that you will hear about from Dr. McDermott to see if that may be a viable treatment option for patients with kidney cancer in the future.

Audience: “After ablation, do you usually see necrosis in the body of the tumor? Can you see that during imaging?”

Kamar: You can see that afterwards, and typically more common with cyro. You see necrosis, coagulative necrosis. Typically it is coagulative to the tumor. You see that on the pathology, when you end up removing that tumor later on. So what we see is absence of contrast enhancement. The tumor before treatment was lighting up when you give contrast. After the procedure, it stays dark. That is our best indicator, other than biopsy, that the tumor is really treated by radio frequency. We don’t see really necrosis on imaging quite like for larger tumors like Dr. Woods showed earlier.

Audience: “So during subsequent imaging, you might see necrosis?”

Kamar: You might but typically what we look for is absence of enhancement. Necrosis is not something we reliably see or depend upon for follow up.

Audience: “For Dr. Wood, re venous thrombosis, do you insert an IVC filter prior to surgery, I’ve heard, or do you consult with cardiology to get that done. Is that helpful?”

Wood: Definitely that is not helpful before surgery. We have both had patients where some guy on the outside decided it would be helpful to put a filter in the vena cava, just in case a piece of the tumor thrombi broke off. It made surgery extremely, much more difficult. After the thrombus has been removed, in some patients we will leave a vena cava filter, which is like a screen put in the vena cave, so that blood clots below that screen blocks them from going to the lungs. A large pulmonary embolism could be fatal. So patients who do have evidence of a clot down in their legs, we will put a filter in, but if they don’t have any evidence of that, typically we don’t.

Integration of Surgery and Systemic Therapy in the Treatment of Kidney Cancer

Also referred to by the KCA as “Role of Cytoreductive Surgery in the Treatment of Metastatic RCC

UT MD Anderson Cancer Center

KCA National Patient Conference: April 14, 2012

The topic “Integration of Surgery and Systemic Therapy in the Treatment of Kidney Cancer” is near to my heart and in active research at MD A

nderson Cancer Center. The vast majority of patients present to us with locally advanced disease, and the reality is that almost half of patients with kidney cancer will at some time develop metastatic disease, which we all know is currently not curable.

Again, as to stage, the vast majority of patients present to us with locally advanced disease, and the reality is that almost half of patients with kidney cancer will at some time develop metastatic disease, which we all know is currently not curable. (Editor’s note: my stage IV RCC with innumerable lung mets in 2004 is now in remission or “cured”, or close enough to “cured”, that I must add this note. It is still shocking to understand that Stage IV RCC is considered incurable. PZ)

Six years ago, we did not have much to talk about. I could show this slide and sit down. For locally advanced disease, we took out the kidney; for stage IV disease, we took out the kidney and gave systemic treatment, usually cytokines.

Now we almost have too many therapies and don’t know how to use them all. How do we integrate surgery into the context of these treatments that we offer patients with metastatic disease? The sad reailties of this are no home runs. These therapies control the disease for some time in these molecular pathways they target. But in most patients, resistance will develop and they have to move on to the next treatment.

I will talk about how we integrate surgery into systemic treatment in 2012, the role of cytoreductive surgery, and then introduce the idea of pre-surgical therapy, something that we have been studying here at MD Anderson that has shown some promise.

These are two randomized trials, one in the US, the other in Europe, which demonstrate the benefit of patients undergoing cytoreductive surgery. The first is the EORTC trial where patients were randomized to upfront surgery followed by interferon, or by interferon alone.

Next is the SWOG (South West Oncology Group) trial done in the US, again demonstrating the value of undergoing a nephrectomy prior to interferon, versus interferon alone? Frankly, many surgeons referred to this trial as “Surgery followed by ineffective therapy is better than ineffective therapy alone.” You can see by these that the response was only 3-4%.

Now that we have more effective therapy, what is the role of surgery in the context of patients with metastatic disease? We don’t even know why cytoreductive surgery works. Does it just reduce tumor burden? Does it produce some sort of immunologic phenomenon where tumor antigens are exposed or is there an immunological “sink”. Is it an alteration in the metabolic milieu where taking out someone’s kidney and altering the ph in the body somehow is anti-tumoral? Or is taking out the “mother ship”, where some sort of endocrine or paracrine phenomenon that promotes metastases. We have absolutely no idea how it works.

Why not take out everybody’s kidney in the setting of metastatic disease?

The morbidity and side effects can be significant, and people can die from this operation. Though it has been proven beneficial in the context of interferon, and it’s quite possible that patients will spend the majority of their time left on earth recovering from surgery. We’ve seen metastatic disease explode post-operatively. Those patients never even get to go on to targeted therapy after surgery. Perhaps these new therapies will cause the primary tumor to shrink. Maybe we don’t need to take out everyone’s kidneys in the face of metastatic disease.

The French are testing this in their Carmena trial. Patients are randomized to an upfront nephrectomy followed by Sunitinib versus Sunitinib alone. It is a non inferiority study design, and the randomization is 576 patients. There is a problem; the trial is not at all accruing very well. Patients don’t like to have surgery randomized, with a computer saying, “You’re going to have surgery, and you are not”.

With the slow accrual to this trial it will be many years before we have an answer. Sunitinib may not even be relevant at that time. And what are we doing for patients in the meantime? Should I take the kidney out or not?

There is evidence that removing the kidney in the presence of metastatic disease is beneficial, from retrospective data derived from the expanded access trial with Sunitinib. These patients had their

kidney removed, not just cytoreductive surgery, but any time in their past.

They were compared to patients treated with their kidney in place. Patients who had their tumor out had a much better response rate than those treated with their tumors in place.

They also had a better progression free survival (PFS) and a better overall survival (OS) than patients treated with their primary tumors in place. Now this is retrospective, it is biased as it is not clear why the kidney was left in place for any one patient. That might have been because the patient was on death’s door and could not have had the kidney removed. But the data shows a benefit of being treated without having your kidney in place.

Newer data from Dr Toni Chouieri at Dana Farber compares are patients who presented with their primary tumors in place. Those who had the kidney removed prior to targeted therapy had a (overall) survival more than doubled compared to those treated with the primary tumor in place.

Those retrospective and (with patient selection) bias, it gives some guidance there may be some benefit to the removal of the kidney in the setting of targeted therapy.

Summarized from transcript and video; edited for brevity; Many slides were text-only, so recreated to keep files sizes small. Slides recreated in bold lettering and this font to keep the files small.
To view the lecture, please follow this link; you may copy and paste it into your browser.http://www.youtube.com/watch?v=KuJoHPA8sww&list=UUv0VRYOltlNQJLCyNMN61Nw&index=45&feature=plpp_videoBe aware that this is a personal summary of the lectures, and that I am not a medical professional; I am a patient, highly motivated to share the information from this KCA conference.

Dr. Hutson thanks the KCA for the conference and begins:
“The “Management of Toxicities Related to Systemic Therapy for Metastatic RCC” is the bane of our existence in RCC; Dr. Jonasch explained the drugs and their benefits earlier, but with benefits often come side effects.

About two-thirds of these side effects–the toxicities–are mild, and are managed by “supportive care”. This means using medications to ease the toxicities. About 1/3 of the toxicities are severe, and may require a dose modification, a dose holiday, stopping the medication for a few days. For most patients, when the medications are stopped, the side effects go away. Most are not permanent. But when toxicity becomes so severe that it affects quality of life, such that we have to withhold that medication, we may move onto another kind of therapy.

Early recognition is very important. I cannot predict if a patient will develop a toxicity and who will not. We think about that from the research perspective, look at it from a genetic perspective. Studies in the medical literature show that patients’ genetics can affect the patients’ toxicity to the drug. Those studies are called pharmacogenomics or pharmacogenetics–things that make an individual patient or a group of patients more susceptible to a toxicity.

These drugs are approved and used around the world and other populations have different toxicities than patients in the US. Asian populations have more severe hematological toxicities, lowering blood counts than we see in US or western European patients. Clearly there is something that is genetic, a so-called pharmogenomic abnormality. Continued research in that area will help us understand that and predict who is going to have those side effects, and let us choose drugs accordingly.

Early recognition of toxicities is the key to avoiding severe toxicities and avoiding dose reductions. When I start patients on these new therapies, I generally see them every 2-3 weeks for a few months. Thus, we can get a handle on side effects, and have a plan, and intervene as needed. Most side effects manifest in first couple of months of therapy, and are often chronic, ongoing. Once we identify them as potential problem for that patient, then we have a strategy. Then I see that patient less frequently, every 4-6 weeks.

I do encourage the doctors–the community oncologists—to do the same, give early aggressive management of the side effect. But the patient or caregiver needs to pick up the phone and call the doctor or doctor’s nurse early when you have a side effect.

We must also consider long-term effects from these side effects, because patients are living longer. With these agents, used in sequence, patients are living 3-5 times longer than they were just a few years ago. Some patients stay on them for years. One man in my practice has been on Sutent for eight years; there are side effects that he will live with for a long time. These therapies have only been available for 5-6 years, and we are just now learning how to utilize them and their toxicities.

Let’s start first with the VEGF inhibitors, and follow with the mTOR inhibitors. The VEGF inhibitors, include Avastin (bevacizumab), an antibody treatment given by IV, and the TKIs, oral drugs, Sutent (Sunitinib), Votrient (pazopanib), Nexavar (sorafenib) and Inlyta(Axitinib). Their similar toxicities are called class effects.

The effect we see in clinic and most often reported by patients is fatigue. Next are skin/hand foot sores, mouth sores, and diarrhea–daily monster diarrhea. Cardiac concerns, the biggest being hypertension; patients’ hemorrhagic effects don’t seem very big, but epitaxis, i.e., bloody nose is very common.

What is Hand/Foot syndrome? This is palmar plantar erthrodysesthesia, a medical term for painful palms and soles of the feet. Often with calluses form on the pressure points, even cracking. It can get very severe, so the patient is unable to use the hand or the foot, unable to walk. One of my patients had an acute reaction with Nexavar and within three days came to me in a wheelchair. Thankfully that kind of acute reaction is relatively rare. This type of skin toxicity manifests itself in the first 2-3 weeks of therapy, reaching a peak in the first couple of months of therapy.

How do doctors talk about this? You have all heard doctors saying, “grade 1 toxicity, grade 2 toxicity” What does that mean?

To standardize reporting, we use a common language—Common Toxicity Criteria—from the National Cancer Institute, and incorporated into clinical trials. Every doctor can grade the toxicity of a patient in the same way.

Grade 1 would be the mildest toxicity, an eruption, and macular/popular eruption, a bumpy patch. Grade 2 would be the eruption, the bumpy, and now itching, covering less than 50% of the body surface, and Grade 3 would be that eruption, with itching and covering greater than 50% of the body surface area.

For Grades 1 and 2 we use supportive care, and topical emollients and such. For the grade 3 toxicity, very severe, we might hold the drug, let the eruption go away, and potentially, lower the dose.” If it continued or returned, we might change the therapy. Same for Hand/foot Syndrome; Grade 1, minimal changes. Grade 2, more blistering, more peeling, more pain, but not really interfering with your daily activities. Grade 3 is means it interferes with daily activities; you can’t use your hands or feet, affecting your daily life. Same thing; grade 1 and 2, supportive care, and at grade 3, we would be more aggressive.

There is also actually a grade 4 toxicity, which is very extreme side effects and a grade 5, usually considered a side effect that resulted in death.

The next side effect, mucositis or stomatitis, those are mouth sores. We can do a mix of things–tap water or salt & soda mouthwash, that baking soda kind of mouthwash, change toothpaste, as some brands burn.

Lidocaine, such as dentists use can numb the mouth. We don’t want the mucositis to affect the patient’s ability to maintain hydration, the ability to eat, so again, monitor it.

Grade 1; mild side effects–use all the supportive care. Grade 3, very symptomatic, can’t eat, can’t drink, very difficult, and we must consider holding the drug or lowering the dose.

With Hypothyroidism fatigue is the major issue and with some of our drugs, fatigue occurs in 55% -65% of patients.

Fatigue has many possible causes, as it not one thing that causes fatigue in any one individual. Patients can have multiple causes at the same time, including the disease itself, anemia, lowering of the blood count from treatment, and pain medications.

We found the association of these drugs with low thyroid early on at the Cleveland Clinic. Many of these TKIs, at some level or another can affect thyroid function. Doctors need check thyroid functions in patients, especially if they have fatigue. This is something we can easily fix and put a patient on thyroid replacement therapy. Levothyroxine, a thyroid replacement therapy, may be used by a 1/3 or more of patients. Thyroid problems induced by these drugs is very common.

With thyroid issues we are constantly chasing TSH. It fluctuates constantly with these agents. My patients’ TSH is going up and down on their synthroid doses, very common. The graph shown here with Sunitinib therapy, shows the fluctuations of the TSH. If there is problem I am unable to control, I bring in a specialist, an endocrinologist.

Next is dysphagia–difficulty in swallowing–and diarrhea, which is a big side effect, so will review diarrhea.

Grade 1 diarrhea is an increase of fewer than 4 stools over baseline, i.e., normal. In medical texts, it’s considered normal to have a bowel movement about every 36 hours. But if you are used to about 1 or 2 stools per day, and it goes up fewer than 4 more stools than what you normally have, that would be considered diarrhea. Diarrhea is NOT based on liquid stools, but the quantity of stools. So even if you were having formed stools, if you were stooling–having more stools—several times over your normal, that is diarrhea.

Grade 2 is when your stools increase more than 4-6 stools per day, incapacitating. Patients may become dehydrated, so we think about giving IV fluids. Grade 3 diarrhea is the very debilitating diarrhea. With the frequency of the stools, patients are becoming very dehydrated and may need lots of IV fluids, perhaps even hospitalization.

As to treatment, we try over the counter medications, Imodium or prescription meds like Lomotil, or different kinds of diets, the BRAT (bananas, rice, applesauce, toast and similar) diet, different foods. We get nutritionists and dieticians involved. We try to bulk up the food with fiber, with Questran (check with doctor), Fibercon, different fiber products, from over the counter. There are medications that the doctors can try, things like Octreotide or ?????, Sometimes we give pancreatic enzyme pills, that patients with pancreatic issues use. But most patients have grade 1 or 2; we’ll try to control it, not eliminate it. These patients will have diarrhea every day, but controlled with Imodium and Lomotil.

Hypertension is a classic side effect, almost an on-target effect of VEGF inhibition. It is currently being investigated to determine if hypertension can be seen as a biomarker of activity against the cancer. That may mean that patients who develop high blood pressure while in therapy may have a better chance of response to the therapy than those who do not.

We tell other doctors not to lower the dose of the cancer drug, as that is a good sign. Keep that going, but treat the high blood pressure. Do that with blood pressure drugs, the kind patients are already on.

If I have a patient who that is having difficulty, and we are using 2 or 3 blood pressure drugs, I will refer him to a nephrologist, a kidney specialist, who specializes in high blood pressures issues or a cardiologist to help me. But in general, it is very rare to find a patient who cannot be on these therapies due to blood pressure issues. If the patient is already on blood pressure medications, he is going to have troubles down the road. We identify that before starting the therapy, be proactive. Have the patient check their blood pressure daily, keep a diary, review that, have a plan so they can stay on their therapy.

Epitaxis–bloody nose seems to happen quite a bit, especially when seasons change. The listed medications don’t have direct effect on the mucosal lining, but may when patients have inflammation., if they don’t make the blood is more thin. We use bedside humidifiers, Vaseline in the nose, nasal steroids and different agents to try to control it. I’ve only had one or two patients who had a major problem.

If you are predisposed to hemorrhoids , there may be more bleeding than usual. Try the topical products here, like Preparation H. Gingival bleeding, bleeding from the gums when you brush your teeth. Key thing that will interest surgeons is wound complications. If you are to have a surgical procedure, tooth extraction, or a surgical procedure that normally considered minor, you have to be concerned there could have complications with bleeding. Sometimes we’ll have the patient hold the medication for a few days before a minor procedure.

With a major surgical procedure, the literature is very controversial about the length of time, generally a few days, but that is at the discretion of the surgeon, and their comfort level. You would resume the medication once there was appropriate wound healing. Usually the surgeon will visit with you a week or 10 days, and remove staples and that would be a good time to resume.

A lot of side effects and it sounds bad, but I share some hope here. Tolerance may develop with long-term use. This is information from Nexavar from the original trial. The first, HFSR, the hand/foot syndrome is shown with the axis as cycles, 1-5, a month of therapy. The high peak that patients seem to have in HDFS is in the first cycle and fewer as the weeks go by, they develop resistance. Same with the skin rash; same with diarrhea, hard in the first cycle, more controlled in the end. The fatigue is similar. So a tolerance can develop, but you have to fight through the side effects.

Now about the mTOR inhibitors. We have Torisel or temsorilimus, a IV weekly medication and Afinitor or everolimus, the oral medication. Just as with VEGF inhibitors, these have class effects associated with both.

We see fatigue, skin rash, but no hand/foot syndrome. It’s not that severe life/quality of life syndrome that we see with the VEGFs inhibitors. You can get a mucositis, less severe that the VEGF inhibitors or diarrhea, but that is essentially it. You do not get the high blood pressure issues as with the VEGF inhibitors. Generally patients feel that the mTOR inhibitors are more tolerable, less difficult, less severe side effects than the VEGF inhibitors.

Unique about this class are hyperglycemia–raising of the blood sugar and elevation of cholesterol. If you have diabetes while taking mTORs, you may have to adjust up your diabetes medications. If you don’t have diabetes, it can sometimes cause a drug-induced diabetes, that requires medication, and is reversible upon stopping the drug. It is reversible side effect, but we have to plan for it.

Hyperlipidemia–elevation of cholesterol levels. I will check cholesterol levels every two months with patients on mTOR inhibitors. If we start to see it rise, we start them on therapy. Many of my patients are already on statins, lipid lowering medications, but it doesn’t seem much of a problem in them. But if a patient isn’t already on, they can develop this.

Hematologic effects. The mTOR inhibitors can lower blood counts, create problems with white blood cell counts, and infections, more than VEGF inhibitors. As a class, mTOR inhibitors are not just used to treat kidney cancer. Long term, and in Europe, they have been used as immunomodulators for transplant patients. They change the immune cells in the body to prevent rejection of organs. For patients with kidney cancer, we change doses, but they can create changes in the immune system and put patients to be at risk for infections, like pneumonia. Doctors have to watch for infections when on Torisel or Afinitor.

A unique side effect to this class is interstitial pneumonitis–inflammation of the lungs. If it occurs, and causes symptoms of coughing or shortness of breath, we need to consider discontinuing therapy. More details on that.

A skin rash with Torisel is usually on the torso. We use a topical crèams, emollients with Benedryl. We try to avoid using steroids, as this drug already has an immune effect and we don’t want to add to it. With a patient who has grade 2, less than 50% of the body affected in a skin rash, I sometimes get a dermatologist to help. If the rare patient develops the grade 3, with more than 50% body surface affected, I would have to consider stopping the medication.

Hyperglycemia has been seen with both the mTOR agents, and we need to monitor blood sugar. Sometimes that means making the patients get a blood monitor, to check their blood sugar medications at home, or start diabetes medication.

Again you can see elevations in triglycerides and cholesterol requiring patients to start on lipid-lowering medications. Those are both reversible when you stop the medication.

We talked about infection. There is a chance of infection with the mTOR inhibitors, so we need to be on alert for that.

Seen here are CT scans of interstitial pneumonitis: in month five there was a development of this nasty-looking infiltrate in the CT scans. That scares everyone when we find this on a CT scan. It could be ones, one; an atypical pneumonia, two; interstitial pneumonitis, a drug side effect, or the cancer. Sometimes, we have to refer patients to a lung specialist for a bronchoscopy to determine what it is. In this case, it was a drug effect, not an infection, and it was not cancer. It was the actual drug inflaming the lungs.

They stopped the drugs, they gave a little burst of steroids, it went away. Later they rechallenged the drug, and the patient went back on the drug, without further recurrence of the interstitial pneumonitis. If I had a patient with interstitial pneumonitis, I would find it very hard to put them back on the therapy. I show this to demonstrate that it is a reasonable side effect to expect, and it is reversible. It manifests itself as an x ray finding or as a cough.

The general recommendations are as shown. Call if there is any side effect which you are uncomfortable with. It is better to call early so you can intervene on it before it becomes a problem.

One devastating complications of venous tumor thrombi is the Budd-Chiari Syndome. The thrombus gets so big that it plugs up the vein, plugs up venous outflow from the liver. Patients present with abdominal pain, ascites, i.e., fluid in the abdomen, edema of lower extremities, enlarged liver, and their liver function tests are all abnormal.

If we take these patients to the operating room, the mortality rate is about 80%. Because of this we no longer take these patients to the OR Instead we will embolize the tumor, cutting off flow of the blood to the tumor. For those patients that regress, we will take them to surgery and they do well.

It is not a very common presentation; we had six patients, two of whom were without evidence of disease after 3 years, using this approach.

NODAL DISEASE

There is a study where patients with localized RCC were randomized to either node dissection or not– to look to see if node dissection improved outcome. This trial showed that patients who had no dissection did no better than those who did not have node dissection. Many will use this in urology community to say that patients who have kidney cancer do not need to undergo node dissection in the absence of metastatic disease.

In a more recent update on this, again, those patients who had a node dissection did no better than those with a node dissection.

But one thing about this trial that troubles me and many in the urologic community is the significant percentage of patients who had very low stage disease. So it gets to the discussion of risk. If you study what you are doing in a low risk population where the frequency of the percent of expected adverse event is so small, you will never see a difference. The problem with this trial is that they need to focus on more advanced stage disease to see if node dissection really makes a difference with kidneycancer.

The group at Mayo did some very elegant studies which showed us where the positive nodes are. So now we go in and do a node dissection on a patient with locally advanced tumor, and we have a very defined area where we know the highest likelihood of metastatic disease is to occur. If we took out all the nodes, the complications would be enormous. We now are directed in where we go looking for nodes and remove them in that fashion.

Side 37 : The group at UCLA did a retrospective study and noted that if you did not have enlarged nodes, it did not matter if you took them out or not. Again, like the EORTC trial, but critics of this argue that it presents low stage disease. But one of the interesting things that did notice that in the patients with positive nodes, that if you took those nodes out they did significantly better. Indicating, even in the absence of systemic treatment, surgery could influence the biology of the tumor.

Slide 38

The group from Mayo identified features that predicted for positive nodes. These include high nuclear grade, the presence of sarcomatoid histology, large tumors or more advanced tumors, or the presence of tumor necrosis.

38a They assessed the primary tumor when it came out of the patient, and if there were 2 or 3 of these features, the risk of having nodal disease was significantly high that they triggered a node dissection. Now they use this prospectively to see if this does let us give better outcomes. This may give us the ability to predict who likely has positive nodes and therefore should undergo a node dissection.

Slide 39 This was a study that was done some years back, but it intrigued me. In patients that had even met and positive nodes, for example, mets to the lungs and positive nodes. Those patients do significantly worse in their prognosis than those without positive nodes. This suggests some adverse biology that is associated with positive node involved.

They also noted that if they could just dissect those nodes, again even in the presence of metastatic disease, they did significantly better than those whose nodes were left in place.

This is a study out of UCLA which shows that patients with metastatic disease do worse in the presence of positive nodes.

Slide 41a We recently looked at our experience (MDACC) with patients with metastatic RCC and positive nodes, limited to clear cell histology. We had 55 with positive nodes compared to 322 who did not. What we noted that those who present with positive nodes do worse than if they do not have them.

Slide 41b But you can see that if they undergo lymph node dissection, even in setting of metastatic disease, they did significantly better, almost a doubling of their survival as patients who did not.

Cytoreductive Surgery Prior to Systemic Therapy for Metastatic RCC

Slide 41c If patients do present with positive nodes, we aggressively resect them, as it significantly impacts on their ability to get treatment. So nowadays, when patients present for cytoreductive nephrectomies, if they have positive nodes, we aggressively resect them, as it significantly impacts their outcome, and their ability to go and get treatment.

Role of Aggressive Surgical Resection in Patients with Positive Nodes in the Absence of Distant Metastases

What about those patients that don’t have metastatic disease but just positive nodes. How do those patients do? We recently looked at our series of patients with positive nodes in the absence of distant metastases, and wanted to asses what factors predicted what affected outcome.

Slide 41d

Out of 3201 nephrectomies, we identified 2521 who did not have metastatic disease, and of those 68 had positive nodes. Surprisingly, we found, that in positive nodes–that the tumor has left the kidney and metastasized–and surgical patients still do pretty well.

Slide 42: There overall survival rate at five years is 37%. You might say, that is pretty low, but that is with surgery alone. But disease specific survival is 39% at five years.

slide44: But when disease recurs, it generally recurs early, at within the first year, but more than a third recur greater than a year out.

Slide 44a: And when patients do recur after this surgery, they usually recur in multiple places with metastatic disease.

Slide45

We wanted to look at factors that predicted for outcomes in these patients. So these are these are the demographics, (editor’s note; the video does not include these charts and slide, which are from the original, unedited video) the vast majority had good performance status, they had local disease, confined to the primary tumor and the overwhelming majority had clinically positive disease. This was not microscopic disease, rather big nodes you can see on CT scans.

What we noted, interestingly, in terms as predictors of overall survival those patients with papillaryhistology had a significantly better outcome, than those with clear cell histology. Those with only one node had a significantly better outcome than those with more than one mode.

When we looked at time to recurrence, again, papillary histology seemed to be a predictor of who would do well. So patients with papillary histology and positive node involvement, we will aggressively resect them.

Slide 45: The multi-variate analysis predicts for overall survival, and papillary histology, the number of nodes positive involved, the presence of sarcomatoid features and status all predicted outcome.

Regards of the time to recurrence, only the number of nodes involved and tumor grade were predictive of outcome in these patients.

(Slides are variations of the same information.)

Secondary Treatments

What about adjuvant therapy in these patients? I already told you that adjuvant therapy doesn’t work. In this particular group, 5 got adjuvant ttreatment and in those 4 patients, it recurred. The important thing is that 85% of these patients had good performance status at three months. What does this say? It means we can do an aggressive surgical resection and patients bounce back very quickly. If they need to go on to get additional treatment, even after this very large surgery.

So these are the feature that predict outcome; papillary histology, number of nodes, sarcomatoid features and ECOG performance status.

I will continue with “Adjacent Organ Invasion” in the next part of the lecture.

Dr. Christopher Wood, of MD Anderson Cancer Center lectured at an April 2012t KCA patient conference on this critical subject. It is a technical discussion, highly important for the patient whose kidney cancer is not longer consider “small and curable” by surgery alone. For greater ease in following this, I have posted this in four segments. My comments will follow in a separate blogs. My hope is that the information is meaningful, so that a patient can learn enough to have a discussion with his/her doctor. Print out the information you have read and give it to the doctor to start that discussion. Some slides were principally text, so I have recreated some to keep the file size down; anything which was not readily converted to text remains as the best available slide.

Consider saying to your doctor, “Here’s what I have been learning, doctor. How does that fit into our plan for my treatment?” That tells your doctor know you are willing to learn and to listen, and to take an active role in your treatment decisions. Unless your doctor deals daily with many kidney cancer patients, he is unlikely to be able to keep up with all the information, ever changing, and ever more complex, about your disease. If the doctor is not willing to listen and learn from the leaders in the field…find another doctor.

Stage is the most important predictor of outcome: the more advanced the stage, the greater risk that the tumor has spread, with distant metastases, making the disease incurable.

This is the staging system we use in 2012, where we stage tumors, assess regional lymph node involvement and look for evidence of metastatic disease. People get hung up on their staging, but this allows doctors to communicate about patients in the same language about how advanced one tumor is. With increasing stage, there is a more locally advanced tumor or metastatic disease.

Let us start with definitions. (Reads slides 2 & 3)

Adjuvant Therapy means some form of therapy– chemo, radiation, vaccine, whatever–after complete surgical tumor resection with the idea to decrease the risk of recurrence of disease. The benefit is that the patient has already had surgery before getting additional therapy, but the downside is that many of those patients may have been cured by the surgery and they may get treatment they don’t really need.

Neoadjuvant therapy is taking some form of therapy, whether chemotherapy, radiation, vaccine, etc. prior to surgery to the primary tumor in hopes the tumor may decrease in size, and decrease the risk of recurrence. The benefit is it may allow the tumor to shrink and make surgery easier. The downside is that the therapy may not be effective and not inhibit metastases, and the primary tumor would not regress, but progress during therapy.

Slide 4

Effective adjuvant or neoadjuvant therapy does not exist for kidney cancer in 2012

Any therapy must be developed in the context of a clinical trial setting, and including a placebo. The only way we make advances is to test what we do now with any advance in the future. And what we now know, as I said, is nothing.Patients have a hard time, with placebo trials. If you participate in such a trial, the treatment you are getting may not be good and the placebo arm, not so bad.

Slide 5 Who should get these therapies? Why not give them to everyone? Anyone taking the targeted therapies today knows the toxicity is significant, and you may treat a significant number of people who really don’t need the therapy. Then if nothing works, why not give it to anyone? Well, we are never going to make advances that way, so it is important that we continue to do research and focus on those who are highest risk for relapse. Should we give it only to those at a highest risk for recurrence? The difficulty how do we define risk, how high is high? So it’s not really clear.

Adjuvant Therapy: 2012

A variety of trials have been performed. Many patients have participated. They include radiation, embolization, energy ablation, a variety of different hormonal therapies, immunotherapies with interferon and interleukin 2, all having been used in an adjuvant setting. There have been a variety of vaccines preparations and we did a Phase III trial of thalidomide trial here. To date, not one ofthese therapies has shown benefit in the adjuvant setting. In fact, many of the patients on the treatment arms did worse than those who were not treated.

Slide 7 What about targeted therapies? That is also the great unknown where things stand with targeted therapies in the adjuvant setting.

Since 2006 there have been seven new agents against kidney cancer. It’s been a revolution. And to be honest, many have benefited from that advance. How do we use these agents in the context of adjuvant therapy?

Slide 8 There is a variety of trials recently completed or in accrual, ongoing. Tthe ARISER Trial used an antibody called G250 against Carbonic Anhydrase IX, and patients were randomized to get either antibody or placebo. This trial completed accrual many years ago, in fact, and we are still awaiting results which leads me to believe that is probably going to be a negative trial.

But this same agent has recently shown promise for use in PET scans for kidney cancer. You can use this as an imaging agent. The patient is infused with the antibody and linked to item 125, and it will show up on x ray, and may potentially detect micro metastases not visible on CT scans. This is actually undergoing FDA approval.

­Slide 10

This is the ASSURE trial we conducted at MD Anderson. It is a randomized, double-blind phase III trial of Sunitinib vs Sorafenib vs Placebo. Patients underwent surgery, then were treated with these agents for 1 year. This trial was completed accrual last September (2011) and we are now waiting for the trial to mature to see whether these agents have any benefit in the adjuvant setting.

Slide 11

One thing that we did learn from this trial is that tolerance for the toxicity associated with targeted therapy in the adjuvant setting is not the same as in the metastatic setting. In this trial 41% of patients stopped therapy early, not because disease returned, or because they finished, but because of toxicity. I think it comes down to an individual assessment of the risks. If I told you that you have a 20% risk of your cancer coming back, versus your 70% chance of your cancer coming back and you are miserable on this therapy, all of a sudden 20% doesn’t look so bad.

My concern about this, because at the end of the day, if this trial matures and it is negative, will it be negative because the agents did not work, or because the patients could not tolerate the side effects. And too many patients stopped the trial early or had dose reductions. I’m afraid it is not going to be interpretable.

Slide 12 This the S-TRAC trial, sponsored by Pfizer, recently completed accrual. It’s randomized between Sunitinib with a placebo for one year. It is estimated results will come out in 2017. That’s the other problem with these trials. Are the agents we are testing now, will they even be relevant in 2017? No one knows.

Slide 13/12

There has been a real problem in accruing to this trial. In fact, we can’t even keep patients on Sorafenib for three years in treatment, never mind adjuvant setting.

Slide 13

This is a trial going on in the US, sponsored by Glaxo-Smith-Kline. This is called the PROTECT trial. Patients are randomized to Pazopanib (Votrient) or placebo for one year. This is primarily open to clear cell patients, here at MD Anderson.

SLIDE 15 A

This is the EVEREST trial, sponsored by the SWOG, going on around the US, with patients randomized to one year of Everolimus (Afinitor) or one year of placebo.

You can see that clinical research is actively ongoing to identify if these agents work in the adjuvant setting. But it is going to take more time to understand from these trials before we know if this is applicable in these setting or as with the other agents, if they remain ineffective.

Slide 16

One other concept we are testing at MD Anderson that I will talk about a bit more in the next talk is a neoadjuvant therapy, testing Axitinib in the neoadjuvant settings. Some in the audience have been on this trial, where patients receive Axitinib for three months and then undergo nephrectomy.

I would like to applaud the patients who participated in this trial. Like to give you an idea how this went the first time we enrolled a patient. Patient comes in with a tumor, curative with surgery, and we say, “We’d like to give you this agent, we don’t know if it will work. In fact, your tumor may grow and metastasize while you are getting this agent. If we took you to surgery tomorrow, we could probably cure you. What do you say?” It was really amazing. The first patient who enrolled in this trial was very brave. But since we have been able to show activity with this agent, enrollment has picked up significantly.”

Dr. Christopher Wood ends the first part of this lecture, with the next section about “The Surgical Management of Locally Advanced Renal Cell Carcinoma.”

I have summarized and edited presentations from an April 2012 Kidney Cancer Association Patient Conference so patients can read and study them.

The original presentations can be found on YouTube offered by the KCA.

Poor resolution slides have been reconstructed

Treatment Options for the Small Incidental Renal Mass

After a brief welcome and expression of appreciation for the KCA, Dr. Karam begins:

“Currently, a small renal mass is defined as smaller than 3 or 4 cm, localized to the kidney, not invasive to other organs. This is a consensus and these definitions can change. Of all Stage I kidney tumors, 43 % are less than 3cm in size. (Some Stage I kidney cancers can be larger than 3cm; other treatments may be more suitable.)

I will discuss three options with patients who present with these types of lesions. The first is active surveillance, the least invasive, the next is energy ablation, and the third is surgical removal. Each will be discussed in the sequence.

First “Active Treatment Options” is energy ablation. This can be done through the skin, percutaneously, laporascopically, or be done “open”. Energy ablation includes two categories, Cryoablation (CA)–freezing the tumor, done laporascopically or through the skin. Alternatively is Radiofrequency Ablation (RFA), typically done percutaneously, or through the skin.

The second major category of active treatment is surgery, the standard of care being an open partial nephrectomy. That removes just the tumor, leaving most of the kidney. It is now more often being done as a robotically assisted partial nephrectomy. Another option is to do it laporascopically, with minimal incisions. Radical nephrectomy, complete removal of the kidney along with the tumor is the lowest on the list. It is the least favorable option, as we try to save the kidney, wherever possible.

AUA (American Urological Association) Guidelines have published some guidelines, based on multiple studies and experts. The standard of care for treatment of small kidney masses is partial nephrectomy. A radical nephrectomy is used only if the mass cannot be removed by partial nephrectomy. A recommendation could be ablation or active surveillance. This will be tailored to individual needs of the patient and the kidney, as to the location of the mass and its characteristics. No one recommendation fits all patients, and each must be discussed and individually tailored.

Next is active surveillance. We don’t use “watchful waiting”, but “Active Surveillance”. We do not to tell someone to go home with your small mass as we don’t need to do anything about it. On the contrary, we have to actively bring the patient to the clinic for CT scans.

What is active surveillance and what does it entail? That means doing no interventions, no surgery, and no procedures that are invasive–active surveillance. Initially we would do imaging at 3-6 months intervals in the first year, subsequently imaging at 6-12 months. There are no rigid guidelines at this point. I always tell my patients to be aware that we have only had small studies with active surveillance, and with short follow-up of 2-3 years. There is a very small potential for spread or metastases while we are doing active surveillance, so every patient has to be informed about all of this.

How often do small masses spread or metastasize? When does it seem to happen? This is a meta analysis of data from 18 studies with almost 900 patients. In only 18 patients of 880 did metastases occur while on active surveillance, a rate of about 2%. This spread occurred almost 3 ½ years after initiation of surveillance, so it does not occur in the first 3-6 months, more on average about 3 ½ years.

“How fast does a mass actually grow?” We know that 23% do not grow at all within 2 years or so. The rest do grow at the growth rate shown.Comparing the growth rate of those who had spread or metastases with those who had none, only 18 patients had spread. The group without spread was typically younger (66 versus 75), with a smaller mass at the initial presentation, 2cm versus 3 cm. The final size in centimeters of those who had spread, those 18 patients, was about 5.9cm. The tumor was quite large at the time when the metastases occurred, and here we started at a size of 3.1 cm.

The growth rate was about 2mm per year for the patients who did not have spread, and about 6mm per year for patients who did have spread. The time on active surveillance was about 2 ½ years.

Of these patients on active surveillance, what happened to them, did they all continue after active surveillance? Over half did remain on active surveillance, over a period of 2-3 years. Fewer than half had delayed intervention. They might have gone to ablation or surgery, and this is over a period of 2-3 years. Others had “delayed intervention, with patients having ablation or surgery on average about two years after starting active surveillance.

The common reason for moving from surveillance to intervention was typically patient concern about the growing mass—patient anxiety. The next reason was enlargement of the mass and the third one was that a patient had some bad medical problem initially not related to the mass. When that problem was solved, and became a good surgical candidate and they are switched to surgery.

Energy Ablation: Radiofrequency

Next is Energy Ablation, a more invasive category which includes radiofrequency and cryoablation.

How does radio frequency ablation work? I usually tell my patients that is basically frying the tumors. The waves from radiofrequency cause friction and movement in the water molecules. This produces heat and destroys the tumor. Cell death occurs in about five minutes after exposure to the RF, with the temperature over 50 degrees Celsius )122 Fahrenheit. This can be monitored during the procedure. We have to achieve temperatures up to 100 (212 F)degrees in order to effectively destroy the tumor with this procedure.

This is a CT scan of the vertebral column and the patient is laying flat on this tummy. This is the kidney, this is the mass, and is CT guided. The interventional radiologist usually puts this thick needle with these tines, typically done under general anesthesia. Though we can do it very infrequently under conscious sedation, but general anesthesia is preferred. A biopsy is typically done at that time and one or more electrodes are inserted. Immediately after the procedure iss done, we do a CT to see that there isn’t any bleeding and to make sure this was treated adequately.

Energy Ablation: Cryolablation

(This is a video which can be seen on the Youtube video.)

The next category of energy ablation is cryoablation or freezing the tumor. This is a picture during laparascopic surgery. You can see them freezing the tumor. This is the kidney here, the tumor here. The tumor here has been marked; the electrodes that go into the tumor, freeze the tumor and form an ice ball.

We use two gases for this procedure. The first is argon, which causes rapid freezing at the tip of the probes, with the temperature dropping to less than 80 degrees Celsius. The second gas is helium, which releases heat as it depressurizes, and it causes very fast thawing of the tumor. This typically repeated twice, two cycles of freezing and thawing. Multiple probes can be used to achieve tumor ablation. With this technique the ice ball can be monitored and you can see the progress with time. This can be monitored by CT or MRI, done percutaneously under guidance, or with an ultrasound when you are doing it laporascopically. or with an ultrasound when you are doing it laporascopically.

Cryoablation—How Does It work?

The Cyroablation acts directly on the tumor cells. It dehydrates the cancer cells, removes all the water from them, which causes damage to the enzymes which are needed for survival by the cells, the organelles and the cell membranes. It also causes the formation of ice inside the cell and kills the cell. But it can also act indirectly, as it targets the cells directly, cutting off nutrition needed for growth. In order to achieve this, very low temperature have to be reached, and to achieve it homogeneously for all of the tumor, the ice ball must extend ½ to 1 cm beyond the margin of tumor to make sure it is completely frozen.

Cryoablation

As to follow up, how do we know it is still working? There will be routine visits to the clinic with medical history, physical exams, chest imaging which is either with conventional radiography, CT and routine blood work.

Follow Up

To follow up on the tumor itself, we typically do a CT or MRI with IV contrast to visualize the tumor. The first follow up is at 6 weeks after the ablation to make sure the ablation was complete and successful and then at 6, 12, 18 and 24 months after ablation.

It does not mean that follow up will end at 24 months. The patient continues with scans for life, routinely, at least once a year after deletion or the treated tumor is stable. So imaging has to continue for years, as we don’t have long term studies with these technologies.

We tend to do more biopsies if the mass is not shrinking well enough, or if it is taking contrast, or it doesn’t look right one year. If the mass is not looking right, we go ahead and do the biopsy to make sure there isn’t any recurrence.

Recurrence defined after ablation can be tricky because the mass is still there. A successful ablation is defined as lack of enhancement of the tumor with the use of contrast. That is why is it very important for the patient to receive and tolerate contrast IV contrast for follow up after ablation. With cryoablation, typically you see tumors shrinking. With Radio Frequency, it doesn’t always happen. That is what makes it trickier, so we have to do biopsies for patients after treatment. And again, the tumor does not always shrink; more typically it does with the cryoablations. Again, radio frequency ablation lesions don’t always shrink, so absence of enhancement is what we look for which is not always ideal.

Now we always discuss with our patients the potential need for biopsy after ablation so this may be expected, though is not routine. Thus, the patient has to be aware of this. We don’t do it routinely, but it is a possibility.

What can predict who is going to have a successful ablation? Tumor size less than 3 or 4 cms is a very good indicator that we will be able to successfully ablate the tumor. If the tumor is exophytic, that the tumor is not deep into the kidney, this is a good indicator. If the tumor is peripheral or not central, that means that the tumor is away from the artery and the vein of the kidney. This is also a very good indicator that we can successfully treat it with ablation.

There are some complications, including pain after the procedure. This is usually an overnight stay; the patient goes home the next day. There could be some numbness or neuromuscular complications. There can be some air around the lung, if the needle had to be inserted close to the lung. This is typically monitored during the procedure.

Seeding from the tumor is exceedingly rare, maybe 1 or 2 cases, so exceedingly rare, nearly unheard of, so this should not be a concern for patients who are willing to go through this procedure. Bleeding can occur, and that‘s why we like to keep patients overnight. Also there could be some strictures or narrowing of the ureter tube that drains the kidney.

So how do we know to recommend RFA or Cryoablation?

We know RFA is considered easier, faster, and safer, but actually has a higher chance of doing damage to the collecting system, the system that drains urine from the kidney. On the other hand, CA has a slightly higher risk of bleeding compared to RF. But it is better for larger tumors, and is good for deep tumors or central tumors. You can monitor live CA with ultrasound or CT to see the ice ball actually grow and treat the whole tumor.

Partial Nephrectomy

The more invasive category is the partial nephrectomy, the actual removal of the tumor, leaving the rest of the kidney in place. The standard had been the open procedure, but nowadays, people tend to do more robotic assisted surgery. You have to have a good surgical candidate for this, both as to the patient’s anatomy and the actual mass. Less commonly used is the pure laparoscopic, just because it is technically challenging and because most hospitals have a robot available.

(VIDEO available on Youtube, about 17 minutes into clip.)

We will show a two minute clip of robotic nephrectomy surgery, courtesy of my colleague. The kidney is here, artery to the kidney here and the vein to the kidney is here. First we need to stop the blood flow to the kidney to do this procedure safely and accurately. A clamp is temporarily placed on the artery and another clamp on the vein, which will completely shut off the blood supply. Here the tumor is literally being carved out of the kidney. Here is the tumor, this is normal kidney, this is tumor, and this is the tumor over here, normal kidney here, so this is what is considered a partial nephrectomy. We check that the mass is excised and then suture the kidney so we can get normal control and prevent bleeding. All you see here is normal kidney. (This is on slightly fast forward–we don’t typically work this fast!)

So now they are bringing back the edges of the kidney together. We use some substance to prevent bleeding which will dissolve on their own: bringing the edges of the kidney back together. And you can see very early on that very little of the normal kidney is removed, just to give a margin to assure that we remove the whole tumor. We remove all the clamps to bring back normal blood supply to the kidney, so this is how the kidney looks. It is pink because it has the normal blood supply. There is no bleeding seen.

Complications might occur in some procedures. This is a large study of almost 500 robotic-assisted partial nephrectomies. Tumor sizes were about 3 cm, so small kidney masses. The total complication rate is about 16%. Complication rates include everything, even slight fevers, so higher than you would expect. Less than 2% of the complications happen during the surgery; most of the complications happen afterwards. About 99% of the surgeries were completed with a robot. Main complications specific to a robotic–assisted partial nephrectomy are bleeding, urinary leakage (1.7%), radical nephrectomy (1.6%), which means removing the whole kidney.

Bleeding occurred in two patients only during the operation, and about 5% of patients while they are still in the hospital. The treatment is relatively simple. Blood transfusion took care of 4% of these patients. About 2% of these patients needed selective embolization, a procedure that is usually done by interventional radiology and done under sedation. This saves the kidney and controls the bleeding as well.

Urinary leakage is found in less than 2%, with treatment typically to put in a stent or a drain or leaving the catheter in longer. None of these patients needed repeat operations or removal of the kidney.

Another complication is conversion to a radical nephrectomy, which occurred in less than 1.6% of patients. This may be due to finding multiple tumors not recognized earlier. In one patient, the tumor could not be found; this happens if the tumor is small and very deep into the kidney. In five patients, a negative margin could not be achieved. That means some cancer was left behind after the tumor was carved out. Then the physician decided to remove the whole kidney to make sure all the cancer was gone. Also, one or more tumors cannot be removed successfully with the kidney left in place. Such complications occur less than 10% under any procedure.

In this table (which could not be captured), but the tumor size was about 3 cm on average. Surgery time was about 3 hours. Blood loss was about 200-300 ccs and hospital stay was about 3 days. This is a different study with complications about 5%. And with positive margins, i.e, a tiny amount of cancer was left, was about 1.6%. The follow up was about four years.

Complications after Treatment Now to compare the rate of complication with RF and cyroablations and surgery: this is from the AUA guidelines; the complication with Cryoablation is about 5%, with RFA about 6%, about 9% with lap partial, and about 6% with open partial and about 3% with complete removal laporascopically, and about 1% with open. All are less than 10% complications.

What about survival without a local recurrence?For cryoablation, it is 90% This is not complete survival, this is living without a recurrence. Again, 90% with cryolablation, with RFA about 87%, and with surgery about 98%.

Renal Function

Partial nephrectomy and RFA has similar renal functional outcomes

No change in GFR

No change in CKD stage

Kidney function is pretty much the same after these procedures, whether you do a partial removal of the tumor or an ablation, so that is not a major factor in decisions.

Active surveillance should be offered to appropriate patients. Patients should be informed that metastases could happen, but typically less than 2% of the time, and it typically takes on average 3-4 years on average. before that would happen. Half of all patients will undergo some treatment eventually, and leave active surveillance.

Survival without Local Recurrence

With the second modality, energy ablation with radio frequency or cryoablation, the chances of survival without local recurrence are about 88-90%, and we have intermediate term data, but not long term follow up on those patients.

However, with surgery you have 98% chance of survival without having a local recurrence to that same kidney. With surgery, we do have long term data as to partial nephrectomy.

A partial nephrectomy is the most definitive therapy. Any patient who is willing to undergo surgery and can tolerate surgery should do have partial nephrectomy for small renal masses. Alternatively, we can offer patients surveillance or ablation. We typically reserve that for that for those with poor kidney function—and we don’t to cause more kidney dysfunction, for those with more have multiple tumors, or for the patient at a high surgical risk or with a poor performance status. That latter patient means he might be a poor surgical candidate due to other health issues, with a heart problem or more dangerous tumors, for example. We can offer surveillance or ablation for those patients. If patient does not want surgery, we can offer two other options. This concludes my talk and I welcome questions.”

In April of 2012, the KCA held a patient conference at MD Anderson Cancer Center, which gathers about 75 patients and caregivers to hear internationally-respected experts about kidney cancer. I attended the conference and had the opportunity to meet with my “Friends on Account of Kidney Cancer”, all of joined by our experience with kidney cancer. We had never seen one another, had to send pix to make sure we could find one another, and greeted each other as long-lost friends.

To make these lectures more meaningful, I have edited each one, after countless hours of review and correction, adding the slides to the lectures and recreating them to make them more easy to email and share. Several friends through my patient connections have read them and found them useful, and I hope you will as well.

The first lecture is by Dr. Jose Karam of MD Anderson, and is presented in its edited form in the next post. Other similar posts will follow until all the lectures are available. With the ASCO conference going on, you will see mention of trials now being published presented at ASCO. These lectures will give you some skills to assess that information , which is now hitting the airways, with the usual lack of perspective and background which we need to understand these new findings.